CLL INTRODUCTION: Treatments

To date, chemotherapy drugs have been the most common form of cancer treatment. Chemotherapy wipes out cancer cells. The treatment works effectively, but in the process, the chemo also kills off healthy cells the body needs. This can result in unpleasant side effects for patients that will vary according to the type of chemo. Most patients handle the drugs easily. Side effects can include nausea, diarrhea, weight loss or a drop in blood counts which can cause infections (a double whammy for CLL patients whose immune functions are already jeopardized).

Two major types of chemotherapy are currently used to treat CLL:

• Alkylating agents including chlorambucil (Leukeran), cyclophosphamide (Cytoxan) and bendamustine (Treanda)
• Purine nucleoside analogs including cladribine (Leustatin), fludarabine (Fludara) and pentostatin (Nipent)

Both types have different mechanisms of killing off the cancer cells. These agents can be given as single agent therapies or can be used in combination with each other, monoclonal antibodies and/or stem cell transplantation.

One advantage is that they provide a more targeted approach than chemotherapy. Monoclonal antibodies bind to a specific protein on the surface of the target cell. When the antibody binds to the protein, this clues the immune system to remove the cell to which the protein is attached (because the immune system perceives it as an invading infection).

Rituximab (Rituxan) is a common monoclonal antibody used for CLL therapy which targets CD20, a protein found on CLL cells. Ofatumumab (Arzerra) also targets CD20, but it targets a different part of CD20 which is proving to be more effective in eliminating CLL cells. It was approved by the FDA in October 2009 for treatment of CLL, adding to the arsenal of CLL treatments. The monoclonal antibody alemtuzumab (Campath) is frequently used as an effective second-line treatment in patients who have relapsed.

There are a multitude of proteins found on CLL cells that can be targeted with monoclonal antibodies. The key is to locate proteins found exclusively or almost exclusively on CLL cells so that healthy cells can be spared. Current investigations will provide more targets for therapy and new monoclonal antibodies in the near future.

More often, steroids are used as a treatment alone or in combination with other therapies. Steroids can help control the leukemia and provide an option for patients who do not respond to chemotherapy.

Splenectomies (removal of the spleen) are occasionally recommended for CLL patients, but generally only if a patient is suffering from discomfort from a large spleen or if the spleen destroys too many red blood cells and platelets.

By combining drugs that have different mechanisms of action, cancer cells can be targeted from different angles and have less chance of surviving. Studies have shown that combining antibodies with chemotherapy allows the two drugs to be more effective than when used alone. Combinations now utilize chemotherapy, monoclonal antibodies, steroids and/or stem cell transplantation.

Currently, the standard combination regimen for frontline therapy of CLL is FCR (fludarabine/cyclophosphomide/rituximab). This combination has led to long remissions for patients and a significant improvement in survival over any previously developed treatment for CLL patients.  FCR has a 70% complete remission rate with some patients staying in remission for over ten years. Although FCR has become the current standard for fit patients, not all CLL patients are benefiting.

“Older” individuals (over the age of 70) make up the majority of CLL patients. Unfortunately, these patients have weaker immune systems and cannot always endure standard treatments. FCR-lite is being investigated to see if the clinical outcome can be maintained while doses are changed and reduced. Both lenalidomide (Revlimid) and HDMP + R, a high dose of methylprednisolone (a steroid) plus rituximab, are tolerated very well by older patients. Lenalidomide is an oral agent with less severe side effects than standard chemo. It is being tested alone and in combination with other drugs in clinical trials.  

CLL patients with Richter’s transformation do not respond well to standard CLL treatments. Only a very small percentage of CLL patients develop Richter’s. Unfortunately minimal research is conducted for these patients. OFAR (oxaliplatin/fludarabine/cytarabine/rituximab) is a fairly new drug combination which is proving to be beneficial for this subtype of patients, as well as Hyper-CVAD + rituximab. 

The idea is that if a patient’s immune system cannot detect and destroy the cancer, someone else’s immune cells can. There is a high-risk associated with SCT, as there is a 40-50% long-term survival rate for CLL patients. Presently, it is the only potential cure for CLL patients, but generally SCT only becomes a treatment option when other treatments are not effective.

Mini-transplants use reduced doses of treatment prior to a patient receiving the transplant. Available statistics show that the mini-transplant is proving to be just as beneficial in outcome as a traditional transplant, but less severe on patients’ bodies. Umbilical cord blood transplants for CLL patients are being studied in clinical trials at the present time and may provide better survival and outcome rates.

There is enthusiastic investigation of ways to teach a patient’s immune system how to attack the CLL cells. One option being tested in a clinical trial takes a patient’s T-cells (a type of immune cell) before the patient receives treatment. The T-cells are then incubated  with stimulating molecules which beef up the cells. The stimulated T-cells are given back to patients after treatment. This gives patients a better chance of fighting infections and may help to delay disease progression. The clinical trial is currently taking place at the University of Pennsylvania and MD Anderson Cancer Center.

A number of vaccines are under development for treatment of CLL. A vaccine called ISF35 inserts genes into the CLL cells which switch them “on”. This stimulates the immune system to destroy the CLL cells. Another approach uses chimeric antigen receptors (CARs) which force immune cells to recognize and destroy CLL cells. One end of the CAR is attached to a T-cell or Natural Killer cell (immune cells). The other end of the CAR then attaches to the CLL cell and brings the two cells in contact with each other. CAR vaccines will be in clinical trials within the next one to two years.

Much has been learned about the biology of CLL. Drugs are being developed which take advantage of this new knowledge. One approach targets and inhibits various signaling pathways needed by the CLL cells to survive. CLL investigators have uncovered the importance of the B-cell receptor (BCR), which is an important protein that sits on the outside of a malignant CLL cell. Through this receptor, the CLL cell is able to receive signals from its external environment. Drugs have recently been developed which target BCR and important proteins used by BCR. These drugs are currently in clinical trials for patients with CLL to study their efficacy.  A major feature of these drugs is that they are given by mouth and have very few recorded side effects.

Another group of compounds interferes with what is called the CLL microenvironment which is a supporting matrix of fibrous tissue and cells. This microenvironment protects the CLL cells and makes them more resistant to chemotherapy or antibodies.  There are new agents that are effective in shaking the CLL cells out of this microenvironment and getting them into the bloodstream, making them more susceptible to therapy. Plerixafor is being investigated in a clinical trial with positive initial results.

Clinical trials allow for data to be collected and analyzed to determine the potential of a new therapy. There are three phases to clinical trials: phase I trials generally have small accruals of patients and represent the first tests of a drug in humans. They are the pilot studies to test the safety of new drugs. Many of these studies show efficacy. Phase II trials help investigators determine adequate dosage and side effects that may not have been present in the smaller population phase I studies. Phase III trials have large enrollments and are almost always multi-center studies. The main purpose is to compare the new drug to the current standard. There are over 525 open clinical trials for CLL world wide according to clinicaltrials.gov.

Most clinical trials require patients to be relatively healthy to qualify for experimental treatments. This poses a problem for CLL patients. Often, the patients who qualify for clinical trials are younger than the average age of CLL patients and have a low co-morbidity index- they are relatively free of other medical complications. There has been little research conducted in patients over the age of 70 or patients who are suffering from complications of heart, lung disease, diabetes or other issues. Additionally, subgroups of CLL patients who are in need of new treatment strategies, i.e. patients with chromosome 17 deletions and Richter’s transformation, have historically been left out of the search for a cure.